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超声内镜或经皮引导下注射的含5-氟尿嘧啶的瘤内TNFerade biologic与放疗联合用于一线治

发布日期:2014-1-29 12:40:27 文章来源:GIE 作者次数:1128
    超声内镜或经皮引导下注射的含5-氟尿嘧啶的瘤内TNFerade biologic与放疗联合用于一线治疗局部晚期胰腺癌:I / II期研究

    背景

    TNFerade Biologic (AdGVEGR.TNF.11D) 一种能在Egr-1启动子的控制下表达肿瘤坏死因子TNF-α)的复制缺陷型腺病毒载体,而这个启动子可由化疗和放疗诱导。

    目的

    确定TNFerade Biologic在治疗局部晚期胰腺癌(LAPC)的最大耐受剂量,以及标准放化疗,初步活性与结合安全性。

    设计

    通过采用EUS或经皮给药方式向局部晚期胰腺癌内注射TNFerade Biologic,一周一次,连续5周,并联合每日50.4 Gy辐射与200 mg/m25-氟脲嘧啶(5-FU),连续5周以上。同时还对不同剂量水平(4 × 109 -1 × 1012粒子单位(PU))进行了研究。

    环境

    多中心学术研究所。

    患者

    50例局部晚期胰腺癌患者进行治疗。

    干预

    不同剂量的TNFerade Biologic用于患者。

    主要测量指标

    依据实体瘤反应评价标准与世界卫生组织标准,通过生物毒性与肿瘤反应测定TNFerade Biologic的耐受性,并由一台中心放射设备审查。本研究还对总生存率和无疾病进展存活率进行了测定。

    结果

    发现3例患者胰腺炎和胆管炎的剂量限制性毒性为1 × 1012 PU4 × 1011PU是最大耐受剂量。实验结果记录了1例患者完全缓减,3例部分缓减,12例病情稳定。7例患者最后做了手术,6例边缘清除,3例存活超过一年。

    局限性

    此研究为一项1/2期非随机研究。

    结论

    TNFerade Biologic是通过內镜超声引导下的细针进行病毒注射或经皮注射的,它与化疗联合治疗局部晚期胰腺癌后TNFerade Biologic的瘤内输送显示有治疗成功的希望。用最大耐受剂量治疗似乎比采用较低剂量治疗有着更好的临床疗效。一般4 ×1011 PU剂量的TNFerade Biologic耐受性良好,且有着激活活性的迹象,我们在本研究随机阶段也对此剂量的TNFerade Biologic进行了测试。TNFerade Biologic的输送不妨碍后续手术切除。

    缩写词:5-FU5 - 氟脲嘧啶;ANC,中性粒细胞绝对计数;CRT,放化疗法;DLT,剂量限制性毒性;DVT,深静脉血栓形成;EUS-FNI,超声内镜引导的细针病毒注射FNI细针病毒注射;LAPC,局部晚期胰腺癌;MTD,最大耐受量;PU,粒子单位;TNF-α,肿瘤坏死因子

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    EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study

    Background

    TNFeradeBiologic (AdGVEGR.TNF.11D) is a replication-deficient adenoviral vector that expresses tumor necrosis factor-α (TNF-α) under the control of the Egr-1 promoter, which is inducible by chemotherapy and radiation.

    Objective

    This study was conducted to determine the maximal tolerated dose of TNFeradeBiologic with standard chemoradiotherapy and preliminary activity and safety of the combination in the treatment of locally advanced pancreatic cancer (LAPC).

    Design

    TNFeradeBiologic was injected into locally advanced pancreatic carcinomas by using EUS or percutaneous administration once a week for 5 weeks together with 50.4 Gy radiation and 5-fluorouracil (5-FU) 200 mg/m2 daily over 5.5 weeks. Dose levels from 4 × 109 to 1 × 1012 particle units (PU) were studied.

    Setting

    Multicentered, academic institutions.

    Patients

    Fifty patients with LAPC were treated.

    Interventions

    Doses of TNFerade Biologic were administered to patients.

    Main Outcome Measurements

    Toleration of TNFerade Biologic was measured through toxicity and tumor response, by using the criteria of the Response Evaluation Criteria in Solid Tumors and the World Health Organization, and was reviewed by a central radiology facility. Overall survival and progression-free survival were also measured.

    Results

    Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3 patients at the 1 × 1012 PU dose, making 4 × 1011 PU the maximum tolerated dose. One complete response, 3 partial responses, and 12 patients with stable disease were noted. Seven patients eventually went to surgery, 6 had clear margins, and 3 survived >24 months.

    Limitations

    This is a Phase1/2 non-randomized study.

    Conclusions

    Intratumoral delivery of TNFerade Biologic by EUS with fine-needle viral injection or percutaneously, combined with chemoradiation, shows promise in the treatment of LAPC. There appeared to be better clinical outcome at the maximal tolerated dose than at lower doses. The dose of 4 ×1011 PU TNFerade Biologic was generally well tolerated, with encouraging indications of activity, and will be tested in the randomized phase of this study. Delivery of TNFerade Biologic did not interfere with subsequent surgical resection.

    Abbreviations:  5-FU, 5-fluorouracil , ANC, absolute neutrophil count , CRT, chemoradiation therapy, DLT, dose-limiting toxicity, DVT, deep vein thrombosis, EUS-FNI, EUS-guided fine-needle viral injection, FNI, fine-needle viral injection, LAPC, locally advanced pancreatic cancerv, MTD, maximal tolerated dose, PU, particle units, TNF-α, tumor necrosis factor-α

     

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